1. Field of the Invention
The present invention is related to the fields of neuropharmacological agents, including agents that are useful in the treatment of eating disorders and agents that stimulate appetite to produce weight gain in both human and animals in need thereof
2. Description of Related Art
Modafinil (C15H15NO2S), 2-(benzhydrylsulfinyl) acetamide, or 2-[(diphenylmethyl) sulfinyl] acetamide, is a synthetic acetamide derivative with wake-promoting activity, the structure of which has been described in French Patent No. 78 05 510 and in U.S. Pat. No. 4,177,290. Modafinil was tested in combination with various agents including apomorphine, amphetamine, reserpine, oxotremorine, hypnotics, yohimbine, 5-hydroxytryptophan, monoamine oxidase inhibitor (I.M.A.O.), and in several behavioral conditions, as described in the cited patents. The conclusion from such tests is that modafinil presents a neuropsychopharmacological spectrum characterized by the presence of excitation with hyperactivity and hypermotility; and by the absence of stereotypy except in strong doses, and as potentiating the effects of apomorphine and amphetamine. A method of preparation of a racemic mixture is described in the ""290 patent and a method of preparation of a levorotatory isomer is described in U.S. Pat. No. 4,927,855 (both incorporated herein by reference). The levorotatory isomer is reported to be useful for treatment of hypersomnia, depression, Alzheimer""s disease and to have activity towards the symptoms of dementia and loss of memory, especially in the elderly.
Modafinil has also been described as an agent with activity in the central nervous system, and as a useful agent in the treatment of Parkinson""s disease (U.S. Pat. No. 5,180,745); in the protection of cerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in the treatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776); and in the treatment of sleep apneas of central origin (U.S. Pat. No. 5,612,378). U.S. Pat. No. 5,618,845 describes modafinil preparations of a defined particle size less than about 200 microns that is more potent and safer than preparations containing a substantial proportion of larger particles. Preparations of modafinil have not been described, however, for use in treating eating disorders, or as appetite stimulants.
The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. Two neuropeptides (orexin-A and orexin-B, also known as hypocretin -1 and -2) have been identified that are derived from a common precursor, preprohypocretin. These peptides are reported to be localized in neurons within and around the lateral and posterior hypothalamus in adult rat brain, and have been shown to bind to and activate G protein-coupled receptors (Sakurai et al., Cell 92:573-585, 1998), and are also reported to stimulate appetite and food consumption (Wolf, Nutr. Rev. 56: 172-173, 1998). Although the appetite stimulating neuropeptides may prove useful for stimulating appetite, and/or promoting weight gain in a variety of situations, such as eating disorders including anorexia nervosa, disease related weight loss, or even in agricultural applications such as promoting faster weight gain in weanling animals, it is difficult to administer peptides that are active in the brain and central nervous system by an oral route. There is still a need, therefore for an oral preparation for treatment of eating, disorders or for promotion of weight gain.
The present disclosure provides a novel use for modafinil in treatment of eating disorders and in stimulating appetite in humans suffering from an eating disorder, or who want or need to gain weight for athletic performance or for cosmetic reasons. The present disclosure also provides novel veterinary or agricultural uses for modafinil in stimulating appetite and increasing the rate of weight gain in animals, particularly young animals or weanlings, and more particularly young animals of species that are utilized for meat. Although the orexin peptides are described as appetite stimulants, modafinil offers certain advantages over those peptides in the compositions and methods disclosed because modafinil has been shown to be an effective oral treatment with activity in the brain and central nervous system. As such, modafinil is more convenient to administer than a peptide agent would be, which must often be injected in order to be effective.
As such, the present invention may be described in certain embodiments as a method of treating an eating disorder in a mammal comprising administering to said mammal an amount of a modafinil compound effective to stimulate the appetite of said mammal. The present invention may also be described in certain embodiments as a method of promoting weight gain in a mammal comprising administering to said mammal an amount of a modafinil compound effective to stimulate the appetite of said mammal.
An aspect of the present disclosure is also a method of increasing appetite in a mammal comprising administering to said mammal an amount of a modafinil compound effective to increase the appetite of said mammal. A further aspect of the present disclosure may also be described as a method of treating a mammal suffering from the symptoms of an eating disorder comprising administering to said mammal a pharmaceutical composition comprising a modafinil compound in an amount effective to stimulate orexin activity in the central nervous system of said mammal.
In certain preferred embodiments of the invention, a mammal or subject to receive a modafinil compound may be a human or an animal, and in particular animals such as a bovine, ovine, caprine, or porcine animal. Such animals are also described as cows, calves, pigs, sheep, or goats, and may include various exotic animals that are raised for agricultural uses, for showing or for hunting, for example. It is understood that the present methods would also be useful for enhancing appetite in pets, such as dogs and cats, for example.
In certain preferred embodiments, a modafinil compound as used in the practice of the disclosed compositions and methods is modafinil. As disclosed herein and as used in the compositions and methods of the present invention, a modafinil compound may include a racemic mixture, and may be in an acid form, such as a metabolic acid of modafinil or a benzhydrylsulfinylacetic acid, a sulfone form, a hydroxylated form, a conjugated form such as a modafinil compound conjugated to a protein, a polysaccharide, a glucuronide or a sulfate, or a polymorphic form, it may include compounds containing isosteric replacements of the phenyl groups of modafinl, and polymorphic species or analogs of modafinil, or derivatives of cogeners and prodrugs, particularly those preparations that stimulate activity in the TMN, or that activate orexin neurons in the central nervous system when administered to a mammal. Prodrugs are known in the art as compounds that are converted to the active agent (modafinil) in the body of a subject.
The compositions and methods disclosed herein are useful, in certain embodiments, in the treatment, stabilization, or prevention of eating disorders in mammals, or humans, for example, and in particular in the treatment of anorexia nervosa, binge eating disorder, bulimia nervosa, undernutrition or malnutrition due to infancy, pregnancy or lactation, old age, or chronic disease, or in wasting associated with various diseases such as AIDS or AIDS Related Complex, for example.
Effective dosages as described herein include, but are not limited to an amount from about 1 to about 400 mg, or from about 100 to about 400 mg, or about 200 mg per daily dose for an adult human, or an equivalent dose for a human child or an animal. It is well known in the pharmaceutical art to prescribe drugs based on the body weight of a subject and calculating doses for humans or animals based on the present disclosure is well within the skill of a practitioner in the art. In an alternate method of describing an effective dose, an effective amount may be described, in certain embodiments as an amount that is effective to achieve a serum level of modafinil of from about 0.05 to about 20 .g/ml, or from about 1 to about 20 .g/ml in an animal or a human.
Preferred formulations include compositions in which a modafinil compound is formulated for oral administration, or more preferably those inn which a modafinil compound is formulated as a tablet. Preferred tablets contain lactose, corn starch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc in any combination. It is also an aspect of the present disclosure that a modafinil compound may be incorporated into a food product or a liquid.
In certain aspects, the present disclosure includes pharmaceutical compositions in unit dose form, for use in treating an eating disorder in a subject susceptible to the development of or suffering from an eating disorder, which comprises:
an amount of a modafinil compound such that one or more unit doses thereof are effective to stabilize or improve the symptoms of an eating disorder in said subject upon periodic administration.
Also in certain aspects, the present disclosure includes veterinary compositions in unit dose form, for use in increasing appetite in an animal, which comprises:
an amount of a modafinil compound such that one or more unit doses thereof are effective to increase the appetite of an animal upon periodic administration.
An aspect of the present disclosure may also be described as a therapeutic package for dispensing to, or for use in dispensing to, a mammal being treated for an eating disorder, comprising:
(1) one or more unit doses, each such unit dose containing an amount of a modafinil compound such that said one or more unit doses thereof are effective to stabilize or improve a symptom of an eating disorder in said mammal upon periodic administration and the unit doses being administered periodically, and
(2) a finished pharmaceutical container therefor, said container containing (a) said unit dose or unit doses and (b) labeling directing the use of said package in the treatment of said mammal.
Although the compositions and methods disclosed herein have been described in light of certain preferred embodiments, it is understood that the modafinil compounds described herein may be orally administered with an inert diluent or an assimilable edible carrier, for example. The compositions may also be enclosed in hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds such as modafinil may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, although tablets are the generally preferred method of administering, modafinil. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit.
The tablets, troches, pills, capsules and the like may also contain any of the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin, excipients, such as dicalcium phosphate, a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring, for example. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup of elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compounds may be incorporated into sustained-release preparation and formulations.
In certain embodiments, the disclosed compositions may be formulated to be administered by use of a skin patch, or transdermal delivery system. The administration of the modafinil compositions described herein transdermally may be accomplished by any of a number of systems known in the art. Examples of systems that may be adapted for use with the compositions described herein include those systems of transdermal administration described in U.S. Pat. No. 4,816,252; U.S. Pat. No. 5,122,382; U.S. Pat. No. 5,198,223; U.S. Pat. No. 5,023,084; U.S. Pat. No. 4,906,169, U.S. Pat. No. 5,145,682; U.S. Pat. No. 4,624,665; U.S. Pat. No. 4,687,481; U.S. Pat. No. 4,834,978; and U.S. Pat. No. 4,810,499 (all incorporated herein by reference.
These methods typically include an adhesive matrix or drug reservoir system and may include a skin permeation enhancement agent such as ethanol, polyethylene glycol 200 dilaurate, isopropyl myristate, glycerol trioleate, linolenic acid saturated ethanol, glycerol monooleate, glycerol monolaurate, n-decyl alcohol, capric acid, and certain saturated and unsaturated fatty acids, and their esters, alcohols, monoglycerides, acetate, diethanolamides and N,N-dimethylamides (See for examples, U.S. Pat. No. 4,906,169).